PROJECT SUMMARY Aging is associated with an increased incidence of cancer, including blood cancers like acute myeloid leukemia. Many leukemias have been shown to initiate in the hematopoietic stem cell (HSC), which is responsible for regenerating all blood lineage cells over the life of an individual. This places the HSC at a particularly vulnerable position in disease processes. Proper functioning of the HSC requires a balance between self-renewal to maintain the HSC pool and differentiation to generate hematopoietic cells. This balance is a result of dynamic interactions between the HSC and factors in its environment, all of which display a functional decline with age, and thus can contribute to dysfunction and disease with age. One such environmental factor is inflammation. Aging is associated with low-grade, chronic inflammation, and many aging-associated diseases, like cancer, have been linked to chronic inflammation. Further, inflammation can impact the balance of HSC self-renewal and differentiation. This proposal aims to draw connections between the correlative findings that i) HSCs and their microenvironment decline with age, ii) inflammation increases with age, and iii) leukemia incidence increases with age. Preliminary data suggest that inhibiting aging- associated inflammation prevents aging-associated decline in HSC function. Our lab proposes the Adaptive Oncogenesis Model, an evolutionary model to explain the exponential increase in cancer incidence with age. We propose that in a young, healthy individual, cells and the environment are optimally fit, such that the chance a phenotype-altering mutation will improve fitness is low. This suppresses the development of cancer in young individuals. However, with age, perturbations in the microenvironment, such as tissue damage or inflammation, can decrease the fitness of cells and their surrounding tissue, thus increasing the chance that a phenotype-altering mutation will provide an adaptive benefit. This can result in expansion of cells carrying mutations and thus drive the development of leukemia. This proposal will address whether reducing aging-associated chronic inflammation can prevent aging- associated decline in HSC function (Aim 1), whether aging results in increased selection for oncogenic mutations in HSCs (Aim 2A), and whether reducing aging-associated chronic inflammation can prevent oncogenic adaptation due to age (Aim 2B). Findings from this research could uncover novel ways to prevent and treat leukemia.